NINJ2基因对肥胖表型的调控及其机制研究

Obesity is one of the most important health issue, and the pathology of obesity is complex. Identify the novel causal gene and molecular pathway is the key of revealing the mechanism of obesity. In previous study, the team of the applicant studied the function of NINJ2 gene，and found that it related with inflammation. What is more, the NINJ2 transgenic mice showed serious phenotype of obesity, and NINJ2 KO mice can antagonize the diet induced obesity. These results showed that NINJ2 is a novel susceptibility gene of obesity. The purpose of this project is to reveal the mechanism of NINJ2 caused obesity. For this purpose, first we will perform genetic study in human population, and analyze the relationship between the expression and the variant of NINJ2 with obesity in human. Second, we will analyze the phenotype of NINJ2 TG mice and KO mice, and study the effect of NINJ2 to metabolic traits and the mature, distribution and function of adipose tissue. Third, we will study the effect of NINJ2 to the proliferation,differentiation,mature and hypertrophy of adipocytes. Finally, we will study the pathway and interacted protein of NINJ2. The results of this projects will help us to understand the relationship and the details among NINJ2, inflammation and obesity. This project will also facilitate to identify novel methods and targets of treatment and prevention of obesity.

肥胖严重影响人类健康，其病因复杂，发现新的肥胖基因和通路是了解肥胖的关键。申请人课题组前期研究发现NINJ2转基因小鼠出现严重肥胖表型，基因敲除小鼠则能够抵抗饮食诱导的肥胖，提示其是一个新的肥胖基因，细胞学研究还发现其与炎症反应相关。本课题拟首先通过人群研究，分析NINJ2对肥胖表型的决定性作用。其次通过小鼠模型，研究NINJ2对各种代谢表型的影响，分析其对炎症反应和肥胖相关病理生理过程的作用，探究其调控肥胖的病理生理机制。再次将分析NINJ2对脂肪细胞增殖、分化、成熟与肥大的影响，研究其对脂肪细胞炎症反应的作用，揭示其调控肥胖的细胞学机制。最后将分析NINJ2上下游分子信号通路及互作蛋白，明确其调控肥胖的分子信号通路。通过以上研究，从群体－个体－组织－细胞－分子层面，阐明NINJ2与炎症反应调控肥胖的详细机理及分子机制，为发现新的肥胖防治手段和治疗靶点打下基础。

肥胖严重影响人类健康，其病因复杂，发现新的肥胖基因和通路是了解肥胖的关键。申请人课题组前期研究发现NINJ2转基因小鼠出现严重肥胖表型，基因敲除小鼠则能够抵抗饮食诱导的肥胖，提示其是一个新的肥胖基因，细胞学研究还发现其与炎症反应相关。 本课题首先通过体外脂肪细胞分化实验，发现脂肪细胞分化与成熟过程中，NINJ2表达量升高，提示NINJ2在脂肪分化过程中可能发挥作用。脂肪前体细胞高表达NINJ2后，可通过激活PPAR-γ、CEBP-αFABP4等脂肪成熟与分化关键通路通路，促进脂肪细胞分化过程。同时，发现NINJ2通过TLR4-NOS-ROS信号通路，调控炎症反应通路，促进内皮细胞-免疫细胞互作。此外，还发现NINJ2与BCL2L13互作，调控脂肪细胞中的线粒体动态，影响白色脂肪棕色化过程。最后，还发现NINJ2基因可调控内皮细胞损伤等过程，增加肥胖后血管损伤等过程。以上研究结果从个体-组织-细胞-分子层面，初步揭示了NINJ2调控炎症反应和肥胖的分子机制。